Obesity is a leading risk for arterial hypertension. In the past fie years, there have been dramatic advances in understanding the genetics and molecular physiology of obesity with the discovery of the leptin and melanocortin systems. This proposal is designed to advance understanding of the physiologic mechanisms and role of leptin, melanocortins, and agoutin protein in regulation of sympathetic activity, vascular reactivity, and arterial pressure. To evaluate the physiologic mechanisms and role of leptin in regulation of arterial pressure, one set of studies will address these questions. 1. Does loss of a physiologic sympathetic action of leptin result in lower arterial pressure in ob mice? 2. Does leptin deficiency or resistance decrease renal norepinephrine spillover in leptin-deficient and resistant mice? 3. Does leptin deficiency or resistance decrease renal norepinephrine spillover in leptin-deficient and resistant mice? 3. Does neuropeptide Y contribute to the decreased sympathetic activity and arterial pressure in db mice? We have also recently demonstrated that agouti fellow obese mice have elevated arterial pressure. This murine model is characterized by widespread over- expression of agouti protein, an endogenous antagonist of melanocortin-4 receptors (MC4-R). Recent studies have shown both sympathetic and vascular effects of MC4-R and agouti protein. In order to explore the mechanisms underlying elevated arterial pressure in agouti mice, we will address the following questions: 1. Do obese mice lacking functional MC4-R have elevated arterial pressure. 2. Do agouti obese mice have selective leptin resistance with preservation of the sympathoexcitatory actions but loss of the peptide and weight reducing actions of leptin; and 3. What are the mechanisms underlying the direct vascular effects of agouti protein? These studies will use state-of-the-art techniques including measurement of regional norepinephrine turnover and continuous direct radiotelemetric measurement of arterial pressure in conscious unrestrained mice. This proposal promises to advance our understanding of novel mechanisms that may underlie obesity-induced alterations in arterial pressure.